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. 2001 Apr;8(4):316-20.
doi: 10.1038/86188.

Human cystatin C, an amyloidogenic protein, dimerizes through three-dimensional domain swapping

R Janowski  1 , M Kozak, E Jankowska, Z Grzonka, A Grubb, M Abrahamson, M Jaskolski
Affiliations

Human cystatin C, an amyloidogenic protein, dimerizes through three-dimensional domain swapping

R Janowski et al. Nat Struct Biol. 2001 Apr.

Abstract

The crystal structure of human cystatin C, a protein with amyloidogenic properties and a potent inhibitor of cysteine proteases, reveals how the protein refolds to produce very tight two-fold symmetric dimers while retaining the secondary structure of the monomeric form. The dimerization occurs through three-dimensional domain swapping, a mechanism for forming oligomeric proteins. The reconstituted monomer-like domains are similar to chicken cystatin except for one inhibitory loop that unfolds to form the 'open interface' of the dimer. The structure explains the tendency of human cystatin C to dimerize and suggests a mechanism for its aggregation in the brain arteries of elderly people with amyloid angiopathy. A more severe 'conformational disease' is associated with the L68Q mutant of human cystatin C, which causes massive amyloidosis, cerebral hemorrhage and death in young adults. The structure of the three-dimensional domain-swapped dimers shows how the L68Q mutation destabilizes the monomers and makes the partially unfolded intermediate less unstable. Higher aggregates may arise through the three-dimensional domain-swapping mechanism occurring in an open-ended fashion in which partially unfolded molecules are linked into infinite chains.

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Comment in

  • More than just mad cow disease.
    [No authors listed] [No authors listed] Nat Struct Biol. 2001 Apr;8(4):281. doi: 10.1038/86132. Nat Struct Biol. 2001. PMID: 11276238 No abstract available.
  • Trading places.
    Newcomer ME. Newcomer ME. Nat Struct Biol. 2001 Apr;8(4):282-4. doi: 10.1038/86134. Nat Struct Biol. 2001. PMID: 11276239 No abstract available.

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